Project Summary Currently available antidepressants produce remission in approximately two-thirds of patients with major depressive disorder (MDD), a disorder affecting over 10 million people in the US each year. This leaves an enormous number of depressed patients without the opportunity for a mentally healthy life, and demonstrates that novel therapeutic strategies to treat depression are sorely needed. A better understanding of the brain pathology associated with MDD will yield critical insights for the development of novel therapeutic approaches. Pathology of white matter (WM) in MDD has been demonstrated in in vivo imaging and postmortem brain tissue studies, but the molecular and cellular basis of WM pathology in MDD are poorly understood. The myelinating oligodendrocyte (OL) is a cellular resident of WM; OLs provide insulation, and trophic and metabolic support to axons passing through WM. Hence, OLs support neurotransmission and disruption of OL function has deleterious consequences on axonal conduction and transport. Interestingly, OLs are normally highly susceptible to oxidative damage. We previously have shown that OLs from MDD brain donors demonstrate reduced gene expression of antioxidant enzymes that protect cells from oxidative stress. Here, strong preliminary data are provided showing that OLs in WM from MDD brain donors demonstrate elevated DNA oxidation and upregulation of DNA base excision repair. Based on these findings, we hypothesize that the consequences of the cellular vulnerability of OLs to reactive oxygen species in MDD is increased oxidation of DNA in WM, and an elevated activation of DNA base excision repair that results in facilitation of inflammatory pathways and increased consumption of cellular energy supplies. Because OLs are critical components of saltatory conduction along axons, compromised OLs could disrupt neural activity related to regulation of emotion in depression. The aims of this study will directly test our hypothesis by using postmortem brain tissues already collected from behaviorally characterized human brain donors (MDD and matched psychiatrically normal control) for whom psychiatric/behavioral status at the time of death was confirmed by psychiatric autopsy. The proposed research will 1) investigate oxidative damage to DNA in brain WM OLs by measuring DNA oxidation and gene expression of base excision repair and related enzymes 2) interrogate deleterious cellular events resulting from upregulation of the DNA base excision repair process, e.g. cellular accumulation of toxic metabolic products (poly [ADP-ribose] polymers), cellular depletion of an energy source (NAD+) used in DNA repair, and increased expression of inflammatory mediators (NF-?B and related cytokines) facilitated by key base excision repair enzymes. A rigorous consideration will be made of potentially contributing factors to changes in dependent variables in MDD, such as suicide/suicidal behavior, other behavioral dimensions, antidepressant exposure, and gender. The outcome of this research has the potential to reveal novel therapeutic targets to improve the treatment of depression.